Fumarate esters, including dialkyl fumarates and monoalkyl fumarates are pharmacologically active organic substances useful for treating hyperproliferative, inflammatory, or autoimmune disorders. Both dimethyl fumarate (DMF) and monomethyl fumarate (MMF) activate the nuclear factor erythroid-derived 2-like (Nrf2) pathway in vitro and in vivo in humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. MMF has also been identified as a nicotinic acid receptor agonist in vitro.
TECFIDERA® (dimethyl fumarate) is indicated for the treatment of patients with relapsing-remitting forms of multiple sclerosis. See TECFIDERA® Prescribing Information, January 2017 at 2 (Biogen Inc.), which is incorporated herein in its entirety for the teachings thereof. TECFIDERA ® is formulated as hard gelatin delayed-release capsules containing 120 mg or 240 mg of enterically coated DMF minitablets.
Upon oral ingestion, one methyl moiety of DMF is hydrolysed by esterases to form MMF, the bioactive metabolite. After absorption, MMF is believed to interact with immunocytes in the bloodstream. The primary plasma metabolites of DMF are MMF, fumaric acid, citric acid, and glucose. Monomethyl fumarate is further metabolized in the tricarboxylic acid cycle to carbon dioxide and water.
Fumarate esters produce various undesirable side effects, including flushing, headaches, dizziness, eructation, nausea, vomiting, abdominal or intestinal cramps, and diarrhea. High concentrations of the drug released in the stomach are believed to be responsible for such side effects.
Accordingly, it is desirable to develop oral formulations of fumarate esters that provide enchanced bioavailability and lower doses of fumarate esters as compared to TECFIDERA® and that are equally efficacious for treating multiple sclerosis, psoriasis, or other neurodegenerative, hyperproliferative, inflammatory, or autoimmune disorders.